This invention is in the area of medicinal chemistry, and in particular is (xe2x88x92)-(2S,4S)-1-(2-hydroxymethyl-1,3-dioxolan-4-yl)cytosine (also referred to as (xe2x88x92)-OddC) or its derivative, and its use to treat cancer in animals, including humans.
A tumor is an unregulated, disorganized proliferation of cell growth. A tumor is malignant, or cancerous, if it has the properties of invasiveness and metastasis. Invasiveness refers to the tendency of a tumor to enter surrounding tissue, breaking through the basal laminas that define the boundaries of the tissues, thereby often entering the body""s circulatory system. Metastasis refers to the tendency of a tumor to migrate to other areas of the body and establish areas of proliferation away from the site of initial appearance.
Cancer is now the second leading cause of death in the United States. Over 8,000,000 persons in the United States have been diagnosed with cancer, with 1,208,000 new diagnoses expected in 1994. Over 500,000 people die annually from the disease in this country.
Cancer is not fully understood on the molecular level. It is known that exposure of a cell to a carcinogen such as certain viruses, certain chemicals, or radiation, leads to DNA alteration that inactivates a xe2x80x9csuppressivexe2x80x9d gene or activates an xe2x80x9concogenexe2x80x9d. Suppressive genes are growth regulatory genes, which upon mutation, can no longer control cell growth. Oncogenes are initially normal genes (called prooncogenes) that by mutation or altered context of expression become transforming genes. The products of transforming genes cause inappropriate cell growth. More than twenty different normal cellular genes can become oncogenes by genetic alteration. Transformed cells differ from normal cells in many ways, including cell morphology, cell-to-cell interactions, membrane content, cytoskeletal structure, protein secretion, gene expression and mortality (transformed cells can grow indefinitely).
All of the various cell types of the body can be transformed into benign or malignant tumor cells. The most frequent tumor site is lung, followed by colorectal, breast, prostate, bladder, pancreas, and then ovary. Other prevalent types of cancer include leukemia, central nervous system cancers, including brain cancer, melanoma, lymphoma, erythroleukemia, uterine cancer, and head and neck cancer.
Cancer is now primarily treated with one or a combination of three types of therapies: surgery, radiation, and chemotherapy. Surgery involves the bulk removal of diseased tissue. While surgery is sometimes effective in removing tumors located at certain sites, for example, in the breast, colon, and skin, it cannot be used in the treatment of tumors located in other areas, such as the backbone, nor in the treatment of disseminated neoplastic conditions such as leukemia.
Chemotherapy involves the disruption of cell replication or cell metabolism. It is used most often in the treatment of leukemia, as well as breast, lung, and testicular cancer.
There are five major classes of chemotherapeutic agents currently in use for the treatment of cancer: natural products and their derivatives; anthracyclines; alkylating agents; antiproliferatives (also called antimetabolites); and hormonal agents. Chemotherapeutic agents are often referred to as antineoplastic agents.
The alkylating agents are believed to act by alkylating and cross-linking guanine and possibly other bases in DNA, arresting cell division. Typical alkylating agents include nitrogen mustards, ethyleneimine compounds, alkyl sulfates, cisplatin, and various nitrosoureas. A disadvantage with these compounds is that they not only attack malignant cells, but also other cells which are naturally dividing, such as those of bone marrow, skin, gastro-intestinal mucosa, and fetal tissue.
Antimetabolites are typically reversible or irreversible enzyme inhibitors, or compounds that otherwise interfere with the replication, translation or transcription of nucleic acids.
Several synthetic nucleosides have been identified that exhibit anticancer activity. A well known nucleoside derivative with strong anticancer activity is 5-fluorouracil. 5-Fluorouracil has been used clinically in the treatment of malignant tumors, including, for example, carcinomas, sarcomas, skin cancer, cancer of the digestive organs, and breast cancer. 5-Fluorouracil, however, causes serious adverse reactions such as nausea, alopecia, diarrhea, stomatitis, leukocytic thrombocytopenia, anorexia, pigmentation, and edema. Derivatives of 5-fluorouracil with anti-cancer activity have been described in U.S. Pat. No. 4,336,381, and in Japanese patent publication Nos. 50-50383, 50-50384, 50-64281, 51-146482, and 53-84981.
U.S. Pat. No. 4,000,137 discloses that the peroxidate oxidation product of inosine, adenosine, or cytidine with methanol or ethanol has activity against lymphocytic leukemia.
Cytosine arabinoside (also referred to as Cytarabin, araC, and Cytosar) is a nucleoside analog of deoxycytidine that was first synthesized in 1950 and introduced into clinical medicine in 1963. It is currently an important drug in the treatment of acute myeloid leukemia. It is also active against acute lymphocytic leukemia, and to a lesser extent, is useful in chronic myelocytic leukemia and non-Hodgkin""s lymphoma. The primary action of arac is inhibition of nuclear DNA synthesis. Handschumacher, R. and Cheng, Y., xe2x80x9cPurine and Pyrimidine Antimetabolitesxe2x80x9d, Cancer Medicine, Chapter XV-1, 3rd Edition, Edited by J. Holland, et al., Lea and Febigol, publishers.
5-Azacytidine is a cytidine analog that is primarily used in the treatment of acute myelocytic leukemia and myelodysplastic syndrome.
2-Fluoroadenosine-5xe2x80x2-phosphate (Fludara, also referred to as FaraA)) is one of the most active agents in the treatment of chronic lymphocytic leukemia. The compound acts by inhibiting DNA synthesis. Treatment of cells with F-araA is associated with the accumulation of cells at the G1/S phase boundary and in S phase; thus, it is a cell cycle S phase-specific drug. Incorporation of the active metabolite, F-araATP, retards DNA chain elongation. F-araA is also a potent inhibitor of ribonucleotide reductase, the key enzyme responsible for the formation of dATP.
2-Chlorodeoxyadenosine is useful in the treatment of low grade B-cell neoplasms such as chronic lymphocytic leukemia, non-Hodgkins"" lymphoma, and hairy-cell leukemia. The spectrum of activity is similar to that of Fludara. The compound inhibits DNA synthesis in growing cells and inhibits DNA repair in resting cells.
Although a number of chemotherapeutic agents have been identified and are currently used for the treatment of cancer, new agents are sought that are efficacious and which exhibit low toxicity toward healthy cells.
Therefore, it is an object of the present invention to provide compounds that exhibit anti-tumor, and in particular, anti-cancer, activity.
It is another object of the present invention to provide pharmaceutical compositions for the treatment of cancer.
It is further object of the present invention to provide a method for the treatment of cancer.
A method and composition for the treatment of tumors, and in particular, cancer, in humans and other host animals is disclosed that includes administering an effective amount of (xe2x88x92)-(2S,4S)-1-(2-hydroxymethyl-1,3-dioxolan-4-yl)cytosine (also referred to as (xe2x88x92)-OddC, L-OddC, or (xe2x88x92)-L-OddC), a pharmaceutically acceptable derivative thereof, including a 5xe2x80x2 or N4 alkylated or acylated derivative, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.
In an alternative embodiment, the compounds disclosed herein can be used to treat conditions, specifically those other than tumors or cancer, that involve the abnormal or undesired proliferation of cells. Examples include skin disorders such as hyperkeratosis (including ichthyosis, keratoderma, lichen, planus, and psoriasis), warts, including genital warts, and blisters, as well as any abnormal or undesired cellular proliferation that can be treated with methotrexate. The active compounds disclosed herein can also be used to induce or facilitate abortion.
In a preferred embodiment, (xe2x88x92)-(2S,4S)-1-(2-hydroxymethyl-1,3-dioxolan-4-yl)cytosine is provided as the indicated enantiomer (the L-enantiomer) and substantially in the absence of its corresponding enantiomer (i.e., in enantiomerically enriched, including enantiomerically pure form).
It is believed that (xe2x88x92)-(2S,4S)-1-(2-hydroxymethyl-1,3-dioxolan-4-yl)cytosine is the first example of an xe2x80x9cLxe2x80x9d-nucleoside that exhibits anti-tumor activity. (xe2x88x92)-(2S,4S)-1-(2-Hydroxymethyl-1,3-dioxolan-4-yl)cytosine has the structure illustrated in Formula I. 
It has been discovered that (xe2x88x92)-(2S,4S)-1-(2-hydroxymethyl-1,3-dioxolan-4-yl)cytosine exhibits significant activity against cancer cells and exhibits low toxicity toward healthy cells in the host. Nonlimiting examples of cancers that can be treated with this compound include lung, colorectal, breast, prostate, bladder, nasopharyngeal, pancreas, ovarian, leukemia, lymphoma, head and neck cancer, central nervous system cancer (including brain cancer), cervical carcinoma, melanoma, and hepatocellular cancer.
In an alternative embodiment, a method and composition for the treatment of tumors, and in particular, cancer, or other abnormal or undesired proliferation of cells, in humans and other host animals is disclosed that includes administering an effective amount of a derivative of L-OddC of the formula: 
wherein R is F, Cl, xe2x88x92CH3, xe2x80x94C(H)xe2x95x90CH2, xe2x80x94Br, xe2x80x94NO2, xe2x80x94Cxe2x95x90CH, or xe2x80x94Cxe2x89xa1N and R1 is hydrogen, alkyl, acyl, monophosphate, diphosphate, or triphosphate, or a pharmaceutically acceptable derivative thereof, optionally in a pharmaceutically acceptable carrier, preferably in enantiomerically enriched form.
Although the preferred embodiment of this invention is the use of the active compounds or their derivatives or their salts in the nonnaturally occurring configuration (the L-configuration), the compounds disclosed herein or their derivatives or salts can alternatively be administered in the naturally occurring configuration (the D-configuration) or as a racemic mixture.
Any of the compounds disclosed herein for use in treating tumors, can be administered in combination or alternation with other anti-tumor pharmaceutical agents, to increase the efficacy of therapy. Examples include natural products and their derivatives; anthracyclines; alkylating agents; antiproliferatives (also called antimetabolites); and hormonal agents. Specifically, agents include but are not limited to, nitrogen mustards, ethyleneimine compounds, alkyl sulfates, cisplatin, nitrosoureas, 5-fluorouracil, cytosine arabinoside, 5-azacytidine, 2-fluoroadenosine-5xe2x80x2-phosphate, 2-chlorodeoxyadenosine, tamoxifen, actinomycin, amsacrine, bleomycin, carboplatin, carmustine, cyclophosphamide, cyclosporin, daunorubicin, doxirubicin, interleukin, lomustine, mercaptopurine, methotrexate, mitomycin, thioguanine, vinblastine, growth factors, including GCSF, GMCSF, and platelet growth factors; adriamycin, WP-16, hydroxyurea, etoposide; xcex1, xcex2, and xcex6 interferons, and vincristine. Methods for the administration of effective amounts of these agents are easily determined, or are described, for example, in The Physician""s Desk Reference, latest edition, published by Medical Economics Data Production Company, and Martindale, The Extra Pharmacopoeia, latest edition, published by The Pharmaceutical Press. These methods can be modified routinely to optimize the efficacy of combination and alternation therapy.